Regioselective preparation of substituted pyrimidines

ABSTRACT

The present invention relates to a method of making pyrimidines of formula (III) wherein X1, X2, R1 and R2 have the meanings as defined herein.

FIELD OF APPLICATION OF THE INVENTION

The present invention provides a new method for obtaining efficiently2-amino-5-trifluoromethylpyrimidine derivatives which can be used asintermediates for the preparation of pharmacologically active compounds.

KNOWN TECHNICAL BACKGROUND/AIM OF THE INVENTION

In pyrimidine chemistry, for the majority of nucleophilic substitutionreactions involving 2,4-functionalized pyrimidines and amines it isknown that the first amine addition occurs preferentially (orexclusively) at the more reactive pyrimidine 4-position.

The reaction of pyrimidines of formula I′ (where X is a leaving group;most commonly a halogen, particularly chlorine) and amines of formula IIusually provides mixtures of regioisomers of formulae III′ (2-aminopyrimidine derivatives) and IV′ (4-amino pyrimidine derivatives) (seeScheme 1 below). Examples for such unselective reactions can be found inthe art, inter alia, for the electron deficient2,4-dichloro-5-trifluoromethylpyrimidine.

Thus, usually, the reactions of 2,4-dichloropyrimidine derivatives withamines provide non-selective mixtures of 2-chloro-4-amino-pyrimidinesand isomeric 2-amino-4-chloropyrimidines in such that these reactionsare of limited utility not only due to their lack of selectivity (andits impact on overall yield) but also because separation of theresulting isomers is generally extremely difficult and may requirepreparative HPLC, which is often not desired in a process sequence.

In contrast, there are only few examples where an amine is added to a2,4-dichloropyrimidine in a selective manner to provide preferentiallythe 2-amino-4-chloropyrimidine. The most notable example of this type ofreaction can be found in the international application WO 2005/023780which describes a method for selective addition of an aminefunctionality to the C-2 position of a CF₃-substituted pyrimidine ringin the presence of a Lewis Acid (namely a salt of a metal ion) and anon-nucleophilic base.

However, there remains a need in the art for providing methods forobtaining efficiently compounds of formula III′. Further, there remainsa need in the art for efficient providing compounds of formula III′vis-à-vis unselective regioisomeric mixtures. Further on, there remainsa need in the art for efficient obtaining compounds of formula III′ fromunselective regioisomeric mixtures.

Other aims of the present invention will become apparent to the skilledman from the foregoing and following remarks.

DESCRIPTION OF THE INVENTION

It has now surprisingly been found, that by appropriate choice of thereaction solvent and further reaction particulars, one canpreferentially add an amine functionality to the C-2 position of thepyrimidine ring via nucleophilic aromatic substitution reaction withoutneeding the presence of any Lewis acidic metal ion.

Further, by reacting pyrimidine compounds of formula I′, in which X is aleaving group, such as a halide, arylsulfonate, alkylsulfonate,perfluoroalkylsulfonate, arylsulfinate or alkylsulfinate, with amines offormula II in the presence of a non-nucleophilic auxiliary base using anon-nucleophilic alcohol (such as e.g. tert-butanol, tert-pentanol,neo-pentanol, sec-pentanol or sec-isoamylalcohol, or mixtures thereof)as reaction solvent at an appropriate reaction temperature one canobtain selectively compounds of formula III′. Advantageously, by theappropriate choice of the reaction conditions (e.g. reaction solvent andreaction temperature) one can achieve in this reaction that the desiredregioisomer of formula III′ directly precipitates from the reactionmixture and thus it can be easily separated off (whereas possibleaccompanying undesired isomers may remain in the mother liquor). Via themethods of the present invention described hereinabove and hereinbelowthe compounds of formula III′, in which X is a leaving group asindicated herein, can be thus obtained in good regioselectivity, yieldand/or purity.

The invention thus relates to a process comprising a method of making acompound of formula III

in whichX2 is a leaving group, such asa halide, arylsulfonate, alkylsulfonate, perfluoroalkylsulfonate,arylsulfinate or alkylsulfinate; andR1 and R2 are substituents independently selected from the groupconsisting of hydrogen, an aromatic group and an aliphatic group; ortaken together and with inclusion of the nitrogen atom, to which theyare attached, form a 4-11 membered aromatic or aliphatic ring; saidmethod comprising reacting a compound of formula I

with an amine of formula II [HN(R1)R2]in the presence of a non-nucleophilic auxiliary basein a solvent or mixture of solvents selected from non-nucleophilicalcoholsto form a compound of formula III,in whichX1 is a leaving group, such as a halide, arylsulfonate, alkylsulfonate,perfluoroalkylsulfonate, arylsulfinate or alkylsulfinate.

In a particular embodiment of this invention, X1 and X2 are the same ordifferent and are each independently halides.

In a more particular embodiment of this invention, X1 and X2 arechloride.

A special aspect of the present invention is the abovementioned methodcharacterized in that said reaction is performed as nucleophilicaromatic substitution reaction.

Another special aspect of the present invention is the abovementionedmethod characterized in that said reaction is performed without thepresence of a Lewis acidic metal ion.

Another special aspect of the present invention is the abovementionedmethod characterized in that said reaction is for providingsubstantially (regio)isomerically pure or enriched compounds of formulaIII (such as e.g. better than 90:10, 95:5, 97:3, 99:1 or 99.5:0.5 infavour of the desired (regio)isomer).

Unless otherwise indicated, some terms used above and below to describethe compounds mentioned herein may be defined more closely as follows:

As used herein the term “aromatic”, and specifically, an “aromaticgroup” refers to an aryl or heteroaryl radical as defined herein.

Further, an “aromatic amine” or “aromatic amine radical” refers to anyamine or amine radical bound to at least one sp² carbon atom that ispart of an aryl or heteroaryl group. An amine or amine radical will bereferred to as an aromatic amine or radical even if the amine nitrogenis bound to a hydrogen or an sp³ carbon atom, in addition to the one sp²carbon atom. Thus, for example, —HN(C₆-C₁₀)aryl and—N((C₁-C₆)alkyl)((C₆-C₁₀)aryl) each refer to aromatic amine radicals asdefined herein, despite the fact that each amine nitrogen is attached tonon-aromatic substituents.

The term “aryl” refers to aromatic radicals such as phenyl, naphthyl,tetrahydronaphthyl, indanyl and the like. Unless otherwise mentioned, an“aryl” group may be optionally substituted with 1-3 suitablesubstituents, as defined herein. “Aryl” also refers to a phenyl radicalfused to a non-aromatic heterocycle. Examples of such groups include butare not limited to 2-oxo-indolinyl, chromanyl, indolinyl and2-oxo-3,4-dihydroquinolinyl optionally substituted by 1 to 3 suitablesubstituents.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicgroup usually with one heteroatom selected from O, S and N in the ring,wherein—unless otherwise mentioned—the aromatic heterocyclic group maybe substituted by up to three suitable substituents as defined herein.In addition to said one heteroatom, the aromatic heterocyclic group mayoptionally have up to four N atoms in the ring. Examples of heteroarylgroups include but are not limited to pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g.,1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl,1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl,benzofuryl, indolyl, and the like; optionally substituted by 1 to 3suitable substituents. Alternatively, any ring carbon, —CH—, of theaforementioned heteroaryl group, may be replaced by a group selectedfrom —C═O or —SO₂.

“Heteroaryl” also refers to one of the aforementioned heteroaryl groupsfused to a non-aromatic heterocycle. Examples of such groups include butare not limited to 1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one,3,4-dihydro-1H-[1,8]naphthyridin-2-one,1,3-dihydro-pyrrolo[2,3-b]pyridine and3,4-dihydro-2H-pyrano[2,3-b]pyridine.

“Aliphatic”, and specifically, an “aliphatic group” refers to an alkyl,cycloalkyl, or heterocycloalkyl radical, as defined herein. Aliphaticgroups may be substituted with up to three suitable substituents asdefined herein.

As used herein, the term “aliphatic amine” or “aliphatic amino radical”refers to any amine or amine radical in which the amine or radicalnitrogen atom is bound to an sp^(a) carbon that is part of an alkyl,cycloalkyl, or heterocycloalkyl group. Aliphatic amine groups may besubstituted with up to three suitable substituents as defined herein.

The term “alkyl” refers to C₁-C₁₀ linear or branched alkyl groups (suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl etc.), particularly C₁-C₄ alkyl, optionally substituted by 1to 3 suitable substituents as defined herein.

The term “cycloalkyl” or “cyclyl” refers to C₃-C₁₂ mono, bicyclic ortricyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonan), etc.) that is optionally substituted by 1 to 3suitable substituents as defined herein. Bicyclic or tricyclic speciesmay be fused, bridged or spirocyclic. Thus, examples of “cycloalkyl” or“cyclyl” groups, as defined herein, include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl,bicyclo[3.1.0]hexyl and spiro[2.4]heptyl.

The term “heterocycloalkyl” or “heterocyclyl” or “heterocycle” refers toa mono, bicyclic or tricyclic group containing 3 to 9 carbon atoms and 1to 4 heteroatoms selected from —N, —NR, —O—, —S—, —SO— and —SO₂—,wherein—unless otherwise mentioned—the cyclic radical is optionallysubstituted by 1 to 3 suitable substituents as defined herein. Bicyclicor tricyclic species may be fused, bridged or spirocyclic. Examples ofsuch groups include but are not limited to azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, oxetanyl,thiomorpholinyl, quinuclidinyl, 5-aza-spiro[2.4]heptyl and3-aza-bicyclo[3.1.0]hexyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo oriodo or fluoride, chloride, bromide or iodide.

As used herein, the term “carbonyl” or “(C═O)” (as used in phrases suchas alkylcarbonyl, alkyl-(C═O)— or alkoxycarbonyl) refers to the joinderof the >C═O moiety to a second moiety such as an alkyl or amino group(i.e. an amido group).

When two subsituents attached to a nitrogen atom [such as in —N(R1)R2 or—N(R3)R4 or —N(R5)R6] taken together and with inclusion of the nitrogenatom, to which they are attached, form a cyclic amine, said amine can bea mono, bicyclic or tricyclic ring comprising 3 to 9 carbon atoms and 0to 3 further heteroatoms selected from —N—, —O—, —S—, —SO— and —SO₂—(excluding the nitrogen atom to which the two substituents areattached).

The cyclic amine may be optionally substituted with 1 to 3 suitablesubstituents as defined herein. Bicyclic or tricyclic species may befused bridged or spirocyclic. Examples of such cyclic amines include butare not limited to morpholine, azetidine, piperazine, piperidine,pyrrolidine, indoline, thiomorpholine.

A “suitable substituent” means a functional group which is suited forits intended function. Thus, said “suitable substituent” may mean achemically and, if desired, pharmaceutically acceptable functionalgroup. Such suitable substituents for the aforementioned aryl,heteroaryl, alkyl, cycloalkyl, heterocycloalkyl groups may be routinelydescribed by those skilled in the art. Illustrative examples of saidsuitable substituents include, but are not limited to hydrogen, halogroups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups,alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, alkylthiogroups, arylthio groups, alkylsulfonyl groups, arylsulfonyl groups,heteroarylsulfonyl groups, alkylsulfonate groups, arylsulfonate groups,perfluoroalkylsulfonate groups, alkoxy groups, aryl or heteroarylgroups, cycloalkyl or heterocycloalkyl groups, aryloxy or heteroaryloxygroups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxygroups, HO—(C═O)— groups, amino groups, alkyl- and dialkylamino groups,carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups,alkylaminocarbonyl groups, dialkylaminocarbonyl groups, sulfonamidogroups, alkylsulfonamido groups, dialkylsulfonamido groups, amidogroups, N-acyl groups, arylcarbonyl groups, aryloxycarbonyl groups andthe like, as well as, depending on the intended function, nitro, cyanoand the like. Methylene groups may also be substituted for a carbonyl(C═O) group. Those skilled in the art will appreciate that manysubstituents can be substituted by additional substituents.

In general, if residues, substituents or groups occur several times in acompound they may have the same or different meanings.

The compounds and salts prepared by the methods of the present inventionmay exist in several isomeric forms. All isomeric forms (e.g. allstereoisomeric forms like chiral, enantiomeric, diastereomeric orracemic forms, atropisomeric, tautomeric and all geometric isomericforms) of the compounds and salts thereof prepared by the methods of thepresent invention are intended within this invention, unless thespecific isomer form is specifically indicated.

Thus, e.g. the compounds and salts prepared by the methods of thepresent invention may exist in several tautomeric forms, including theenol and imine form, and the keto and enamine form and geometric isomersand mixtures thereof. The preparation of all such tautomeric forms isincluded within the scope of the present invention. Tautomers exist asmixtures of a tautomeric set in solution. In solid form, usually onetautomer predominates. Even though the preparation of one tautomer maybe described, the present invention encompasses the preparation of alltautomers of the present compounds.

The present invention also includes the preparation of atropisomers ofthe compounds prepared by methods of the present invention. Atropisomersrefer to compounds that can be separated into rotationally restrictedisomers.

The compounds prepared by the methods of the invention may containolefin-like double bonds. When such bonds are present, the compoundsexist as cis and trans configurations and as mixtures thereof and thepresent invention contemplates the preparation of such compounds.

As disclosed herein, compounds of formula III can be prepared byreaction of pyrimidine of formula I and a primary or secondary aminenucleophile of formula II in the presence of a non-nucleophilicauxiliary base in a suitable non-nucleophilic alcohol or mixture ofnon-nucleophilic alcohols as reaction solvent(s) at an appropriatereaction temperature, such as at room temperature, at elevatedtemperature or at the boiling temperature of the solvent(s) used. Themeanings of X1 and X2 (which may be the same or different) on pyrimidineof formula I include those as described above, in particular X1 and X2are the same or different and are each independently halides.Preferentially, X1 and X2 are the same and are chloride.

In an embodiment, the reaction partners are mixed by adding slowly thepyrimidine of formula I, preferably dissolved in a suitable solvent, toa solution of the amine of formula II and the auxiliary base in thereaction solvent(s).

Non-nucleophilic alcohols suitable as reaction solvents for theabovementioned reaction according to this invention include but are notlimited to tert-butanol, tert-pentanol, neo-pentanol, sec-pentanol,sec-isoamylalcohol, or mixtures thereof. Preferentially, theabovementioned reaction is conducted in tert-butanol as reactionsolvent.

Primary or secondary amine nucleophiles of formula II being useful inthe above-mentioned reaction according to this invention include thoseas described above. Particularly suitable amine nucleophiles of formulaII for this reaction with compounds of formula I are primary aromaticamines (e.g. aniline derivatives) as described herein.

Non-nucleophilic auxiliary bases for use in the abovementioned reactioninclude, without being restricted thereto, inorganic and organicnon-nucleophilic bases, such as e.g. inorganic carbonates (e.g. sodiumcarbonate, potassium carbonate, cesium carbonate or the like), tertiaryamines (e.g. triethylamine, N,N-diisopropyl-ethyl-amine or the like) orother nitrogen bases, or alcoholates (e.g. potassium tert-butylate orthe like), or the like. Preferentially, N,N-diisopropyl-ethyl-amine(DIPEA) is used as auxiliary base.

The reaction temperature for this reaction may range from about roomtemperature to about boiling temperature of the solvent(s) used.Particularly, the reaction is run at elevated temperature.Preferentially, tert-butanol is used as the sole reaction solvent andthe reaction temperature may range from about 30° C. to about 80° C.,more preferentially from about 40° C. to about 80° C.

For performing this reaction, it may be suitable to use—relative to theamount of the compound of formula I—a slight deficit of the amine offormula II (typically 0.9-1.0 equivalents) and/or a slight excess of theauxiliary base (typically 1.0-1.2 equivalents).

In a preferred embodiment of abovementioned method according to thisinvention, 2,4-dichloro-5-trifluoromethylpyrimidine is used as reactantwhich may be reacted with an aromatic amine, N,N-diisopropyl-ethyl-amine(DIPEA) is used as auxiliary base, and the reaction is run intert-butanol as reaction solvent at elevated temperature, morespecifically from about 40° C. to about 80° C., especially at about 80°C., to form the corresponding2-amino-4-chloro-5-trifluoromethylpyrimidine derivative as major isomer.

The present invention also relates to processes disclosed herein, saidprocesses may comprise methods of making and/or reacting compounds offormulae I, III and/or III′ as described herein. The present inventionalso relates to the intermediates (including compounds of formula III orIII′), including their salts, isomers and salts of these isomers.

Isolation and purification methods of the compounds obtained are knownin the art and include, for example, removing the solvent(s),precipitation (e.g. with a co-solvent), crystallization, chromatographyon a suitable support material (e.g. normal and reverse phase),extraction, trituration, and the like.

In a preferred embodiment, compounds of formula III obtained areisolated by precipitating it from the reaction mixture. Saidprecipitating may be performed as it is habitual for the skilled person,advantageously by crystallizing from the reaction mixture (especiallywhen tert-butanol as reaction solvent is used), which may occurspontaneously from the hot reaction mixture or which may be induced byknown methods (e.g. by adding seeding crystals and/or cooling) and whichmay be completed by cooling (e.g. to about 30° C.). For removingco-precipitated undesired salts from the precipitate, the precipitatemay be suspended in water, stirred and filtered off. Finally, theproduct obtained may be washed with suitable solvents (such as e.g.tert-butanol and water) and dried.

Illustrative amines of formula II [HN(R1)R2] which may be used in thereaction according to this invention may include—without beingrestricted to—toluidine (e.g. 2- or 4-methylaniline),5-amino-1,3-dihydro-indol-2-one, chloroaniline (e.g. 3- or4-chloroaniline), methoxyaniline (e.g. 4-methoxyaniline or2-methoxyaniline), (optionally substituted amino)-aniline (e.g.N-(4-aminophenyl)-amine), (optionally substituted aminocarbonyl)-aniline(e.g. N-{4-[R6(R5)N—C(═O)]-phenyl}-amine where R5 and R6 are as definedherein), benzylamine, N-(4-methylbenzyl)-amine,N,N-dimethyl-1,4-phenylenediamine, cyclohexylamine,N-(cyclohexylmethyl)-amine, carboxyaniline (e.g. 4-carboxyaniline),piperidine, N-methyl-toluidine (e.g. N-methyl-p-toluidine), or the like.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 2007, 4rd Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2004).

In the reactions described herein, any reactive groups present such ascarboxy-, carbonyl-, hydroxy-, amino-, alkylamino- or imino-groups maybe protected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for a carboxy group may be the methyl-,ethyl-, tert.-butyl- or benzyl-group, particularly thetert.-butyl-group.

For example, a protecting group for a carbonyl group may be an acetal orketal like the 1,3-dioxolane- or the 1,3-dioxane-group.

For example, a protecting group for a hydroxy group may be atrimethylsilyl-, tert.-butyldimethylsilyl-, acetyl-, trityl-, benzyl- ortetrahydropyranyl-group.

Protecting groups for an amino, alkylamino or imino group may be, forexample, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group, and additionally, for the amino group, aphthalyl group.

Thus, e.g., a suitably protected carboxyaniline within the meaning ofthis invention may be, for example, 4-amino-benzoic acid tert-butylester.

Thus, e.g., a suitably protected aminoaniline within the meaning of thisinvention may be, for example, (4-N-Boc-aminophenyl)-amine.

The cleavage of a carboxymethyl- or a carboxyethyl-group can for examplebe carried out hydrolytically in an aqueous solvent, e.g. in water,methanol/water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali base as for example lithium hydroxide, sodiumhydroxide or potassium hydroxide, but preferably sodium hydroxide, oraprotically in the presence of e.g. iodotrimethylsilane, at temperaturesbetween 0 and 120° C., preferably at temperatures between 10 and 100° C.

An acetal or ketal can be cleaved with acetic acid, trifluoroaceticacid, hydrochloric acid, sulphuric acid or pyridiumium-p-toluenesulfonate in mixtures with water or in organic solvents like for exampledichloromethane, 1,2-dichloroethane, tetrahydrofurane, dioxane, tolueneor acetone at temperatures between −20° C. and 150° C., but preferablybetween 0° C. and 120° C.

A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageouslycleaved hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate, tetrahydrofurane, dioxane or glacialacetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 100° C., but preferablyat ambient temperatures between 20 and 60° C., and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzylgroup, however, is preferably cleaved in trifluoroacetic acid in thepresence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas dichloromethane, dioxane, methanol or diethylether.

For example, tert.butyl4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoate obtained bythe method of this invention can be deprotected under acid conditions toyield 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acid.Corresponding procedures are described herein, e.g. such as described byway of example in the following examples.

A trimethylsilyl- or tert.-butyldimethylsilyl-group is cleaved with afluoride reagent like for example tetrabutylammonium fluoride or caesiumfluoride or with an acid like for example trifluoroacetic acid,hydrochloric acid or sulphuric acid in a solvent like e.g.dichloromethane, 1,2-dichloroethane, diethylether, tetrahydrofurane,dioxane, acetonitrile or toluene at temperatures between −50° C. and120° C., but preferably between −20° C. and 80° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine, ethanolamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxane at temperatures between 20 and 50° C.

Amines of formula II or V can be provided as disclosed herein or theyare known or can be obtained analogously or similarly to knownprocedures. Such as e.g. amines of formula V, e.g.cispentacin-isopropylamide, can be obtained as described in WO2007/135036. In a particular embodiment the amines of formula II and Vare both primary amines.

Compounds of formula I wherein both X1 and X2 are the same or differentleaving groups independently selected from the group consisting ofhalide, arylsulfonate, alkylsulfonate, perfluoroalkylsulfonate,arylsulfinate and alkylsulfinate are known or can be obtainedanalogously or similarly to known procedures (e.g., a preparation of2,4-dichloro-5-trifluoromethylpyrimidine is described in WO2005/0123780).

Optionally, prior to further reaction, if the compounds of formula IIIobtainable via above reaction contain a functional group (e.g. —COOH),which may be temporarily protected by a suitable protecting group (e.g.by the benzyl protecting group as benzyloxycarbonyl or by the tertbutylprotecting group as tert-butyloxycarbonyl), the protecting group, ifpresent, may subsequently be removed and the free functional group maybe transformed to another functional group, such as e.g. the carboxylgroup may be reacted with an primary or secondary amine of formula VI[HN(R5)R6] to give the amide group —CON(R5)R6, e.g. with the aid of asuitable coupling reagent for amide bond formation or via the respectivecarboxylic acid chloride, with or without isolation. In anotherembodiment, such conversion of a functional group may be performedlater, e.g. on below-mentioned compounds of formula III′ in which is Xis —N(R3)R4, e.g. after the reaction described herein below.

Compounds of formula III, when reacted with an oxygen, sulfur ornitrogen nucleophile (such as e.g. with primary or secondary amines offormula V [HN(R3)R4] to provide 2,4-diamino products of formula III′ inwhich X is —N(R3)R4), are useful intermediates in the preparation ofpharmacological active compounds, such as e.g. protein kinase inhibitorswhich may be useful in the treatment of abnormal cell growth, such ascancer, in mammals. Compounds such as these are described, for example,in WO 03/030909, WO 03/032997, WO 03/078404, WO 2004/046118, WO2004/048343, WO 2004/056807, WO 2004/056786, WO 2005/026130, WO2005/049033, WO 2005/111023, WO 2005/113515, WO2006/021544, US2006/025433, WO 2006/074057, WO 2006/091737, WO 2006/099974, WO2006/117560, WO 2007/003596, WO 2007/049041, WO 2007/063384, WO2007/072158, WO 2007/096351, WO 2007/115999, US 2007/203161, WO2007/132010, WO 2007/140957, WO 2008/003766, and WO2008/129380.

Amines of formula V or VI are primary or secondary amines, in which R3and R4 or, respectively, R5 and R6 are substituents independentlyselected from the group consisting of hydrogen, an aromatic group and analiphatic group; or R3 and R4 or, respectively, R5 and R6 taken togetherand with inclusion of the nitrogen atom to which they are attached forma 4-11 membered aromatic or aliphatic ring. Amines of formula V or VIinclude, without being limited to, cyclic amines or primary or secondaryaliphatic amines, such as e.g. those mentioned herein, e.g. thosewherein one of R3 and R4 or of R5 and R6, respectively, is hydrogen oralkyl and the other is optionally substituted alkyl, cycloalkyl orheterocycloalkyl as described herein, such as e.g. N-alkyl-amines,N-cycloalkyl-amines, N-heterocycloalkyl-amines, N-alkyl-N-methyl-amines,N-cycloalkyl-N-methyl-amines or N-heterocycloalkyl-N-methyl-amines, eachalkyl, cycloalkyl or heterocycloalkyl optionally substituted as definedherein. Examples of amines of formula V include, without being limited,cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine,(1S,2R)-2-amino-1-cyclopentane carboxylic acid or its amide orisopropylamide, (1S,2R)-2-amino-cyclohexyl-carbamic acid benzyl ester or-carbamic acid tert.butyl ester, and the like. Examples of amines offormula VI include, without being limited,(1-methyl-piperidin-4-yl)-amine, (1-Boc-piperidin-4-yl)-amine,(1-methyl-piperidin-4-yl)-methyl-amine,(1-Boc-piperidin-4-yl)-methyl-amine, piperidine, morpholine,N-Boc-piperazine, N-methyl-piperazine, homopiperidine,N-methyl-homopiperazine, N-Boc-homopiperazine, and the like. The Boc orCbz protecting group may be removed after the reaction to yield the freeamine.

It is to be understood, that certain compounds of formula III or III′ asdefined herein can be converted into other compounds of formula III orIII′, respectively, via synthesis strategies and reactions customary tothe skilled person, such as e.g. comprising one or more of the methodsa) to h) mentioned below.

Therefore, optionally, for example, from compounds of formula III orIII′ as defined herein

a) which contains a carboxyl group, the corresponding ester compoundscan be obtained via esterification reaction, and/or the correspondingamide compounds can be obtained by amidification reaction;b) which contains an ester group, the corresponding free acid compoundscan be obtained via de-esterification reaction (e.g. saponification);c) which contains a primary or secondary amino group, the correspondingamides can be obtained via acylation reaction, and/or the correspondingsulfonamides can be obtained via sulfonylation reaction;d) which contains a hydroxyl group, the corresponding esters can beobtained via acylation reaction;e) which contains an acylated hydroxyl group and/or an acylated aminogroup, the corresponding free alcohols and/or free amines can beobtained via de-acylation reaction;f) which contains a primary or secondary amino group and/or a hydroxylgroup the corresponding N-alkylated and/or O-alkylated compounds,respectively, can be obtained via N-alkylation and/or O-alkylationreaction, respectively;g) which contains a replaceable leaving group, its replacement yieldingthe corresponding substituted compounds can be obtained via nucleophilicsubstitution reaction with N, O or S nucleophiles; and/orh) which contains an oxidizable nitrogen or sulphur atom (e.g. aromaticor aliphatic heterocycles containing an amino- or imino-type ringnitrogen or sulphur atom), the corresponding N-oxides and/or S-oxides(including mono- and di-oxides), respectively, can via obtained by N-and/or S-oxidation reaction, respectively.

The methods mentioned under a) to h) can be expediently carried outanalogously to the methods known to the person skilled in the art or asdescribed by way of example herein.

Finally, optionally, the trifluoromethyl group of 2,4-diamino pyrimidinederivatives of formula III′ in which X is —N(R3)R4 as defined herein maybe hydrolyzed to form the corresponding acids, and, optionally, the thusobtained acids may be subsequently decarboxylated to form thecorresponding des-trifluoromethyl derivatives. Corresponding methods areknown to the skilled person.

The compounds or intermediates obtained can be further reacted withoutisolation or in situ, or they can be isolated and purified in a mannerknown per se, e.g. as described herein, for example by removing ordistilling off the solvent under reduced pressure or by precipitating(e.g. by concentrating the solution, cooling and/or adding anonsolvent), collecting, and, optionally, recrystallizing the residueobtained from one, two or more suitable organic or aqueous solvents(such as e.g. selected from those solvents mentioned below), orsubjecting it to one of the customary purification methods, such as, forexample, column chromatography on a suitable support material.

Unless otherwise noted herein, in general but depending upon thespecific requirements, appropriate solvents for the procedures mentionedherein may be selected from the group consisting of low-molecular-weightaliphatic alcohols, such as methanol, ethanol, propanol or isopropanol;esters, such as ethyl acetate; ketones, such as acetone, methyl ethylketone or methyl isobutyl ketone; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran or dioxane; optionally chlorinatedhydrocarbons, such as n-hexane, petrolether, toluene, methylene chlorideor chloroform; amides or lactames such as e.g. N,N-dimethylformamide orN-methyl-2-pyrrolidone, and nitriles such as e.g. acetonitrile, or thelike, or a mixture of solvents, with or without water, or water alone.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following example. The following exampleserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

Examples Method According to the Invention

a.) A suspension of 71.3 g (552.0 mmol) diisopropyl ethyl amine and 88.9g (460.0 mmol) of 4-amino-benzoic acid tert-butyl ester in 620 mLtert.-butanol is warmed to 80° C. To the obtained solution a solution of104.8 g (483.0 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine in 270 mLtert.-butanol is added slowly in 1 hour. The obtained suspension isstirred for 4 hours at 80° C. The suspension is cooled to 30° C. and 180mL of purified water is added. The suspension is stirred for 30 minutesat 30° C. The precipitate is filtered and washed twice with 170 mL ofwarm tert.-butanol (30° C.) and with 355 mL of purified water. Theproduct is dried at 50° C. As product 103 g (60%) of the desired 2-aminopyrimidine derivative is obtained as slightly yellowish solid with 99.6%purity (HPLC).

¹H-NMR (400 MHz) (DMSO-d₆): δ (ppm)=10.99 (bs, 1H); 8.88 (s, 1H)7.99-7.74 (m, 4H); 1.53 (s, 3H) HPLC ret. Time: 11.135 min.

MS: M+H⁺=374/6

Analytical HPLC Chromatography and Conditions:

Manufacturer: Phenomenex; Column: Synergi Max-Max-RP; Dimension: 150×4.6mm,

Mobile phase: A: 0.3% KH2PO4/pH=4.7. B: Acetonitrile; Gradient: from B(50%) to B (70%) in 8 min. hold for 15 min. at B (70%); Flow rate: 1.5mL/min.; Detection: UV 200 nm;

Temperature: 40° C.; Injection vol.; 2 μL

b.) Optionally in a subsequent step, a mixture of the 2-amino-pyrimidinederivate of formula III obtained in step a) as described above, i.e.4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acidtert.butyl ester (50.0 g; 133.8 mmol), acetonitrile (420 ml) and thionylchloride (31.8 g; 267.6 mmol) is warmed to 70° C. Purified water (4.82g; 267.6 mmol) is added slowly. The reaction mixture is warmed for 1hour at 70° C. After cooling to 2° C. the precipitate is filtered andwashed with acetonitrile (200 ml). The product is dried at 40° C. Asproduct 39.9 g (89.8%) of the corresponding acid chloride derivative,i.e. 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoylchloride,is obtained as slightly yellowish crystals.

¹H-NMR (400 MHz) (CDCl₃): δ (ppm)=8.67 (s, 1H); 8.15 (d, 2H, J=8 Hz);7.81 (d, 2H, J=8 Hz); 7.73 (bs, 1H).

In an alternative variant of step b), the corresponding free acid can beisolated as follows: A mixture of 2-amino-pyrimidine derivate of formulaIII obtained in step a) as described above (10.0 g; 26.8 mmol) andacetonitrile (70 ml) is warmed to 70° C. and a solution of thionylchloride (29.4 mmol) in acetonitrile (30 ml) is added. The reactionmixture is stirred for 1 hour. After cooling to 10° C. purified water(50 ml) is added, the precipitate is filtered and washed with coldacetonitrile. The product is dried at 50° C. As product 8.5 g (97.5%) ofthe corresponding acid, i.e.4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acid, isobtained as white powder.

¹H-NMR (400 MHz) (DMSO-d₆): δ (ppm)=12.67 (bs, 1H); 10.99 (s, 1H); 8.90(s, 1H); 7.94 (d, 2H, J=8 Hz); 7.85 (d, 2H, J=8 Hz).

c) In a further optional step, to a cold suspension or solution of theabove-obtained acid chloride derivative of step b) (e.g. 1.7 eq) in asuitable solvent (e.g. acetonitrile), which may further comprises asuitable inorganic or organic auxiliary base (e.g.N,N-diisopropylethylamine, e.g. 1.4 eq), an appropriate amine of formulaVI (e.g. 1.0 eq) is added. The solution or suspension is stirred andpurified water is added. The cold suspension is filtered (e.g. at about10° C.) and the collected precipitate is washed with a cold mixture ofsolvent/water (e.g. acetonitrile and purified water). The product may bedried at reduced pressure and/or elevated temperature (e.g. about 50°C.). As product the corresponding amide derivative is obtained.

d) In a yet further optional step, the above amide derivative of step c)(e.g. 1.0 eq) and an appropriate amine of formula V (e.g. 1.2 eq) aresuspended or dissolved in a suitable solvent (e.g. a lower aliphaticalcohol such as methanol, ethanol or isopropanol). A suitable inorganicor organic auxiliary base (e.g. N,N-diisopropylethylamine, e.g. 1.1 eq)is added and the reaction mixture is warmed (e.g. to about 80° C.). Thereaction solvent is largely removed and the residue partitioned in anorganic-aqueous biphasic system (e.g. with a suitable ether, ester,ketone, haloalkane or the like as organic solvent) optionally comprisinga suitable inorganic or organic base (e.g. an aqueous sodium carbonateor sodium hydrogen carbonate solution). After phase separation, theorganic solvent is removed and the residue optionally further purified.The corresponding 2,4-diamino pyrimidine derivative is obtained asproduct. In an optional alternative, the initially obtained compound ofstep a) can be reacted with an appropriate amine of formula Vanalogously or similarly as described in step d) to give thecorresponding 2,4-diamino pyrimidine derivative, which can be thenoptionally further reacted analogously or similarly as described in stepb) and c).

What is claimed is:
 1. A method for making a compound of formula III

wherein X2 is a leaving group, and R1 and R2 are substituentsindependently selected from hydrogen, an aromatic group and an aliphaticgroup, or taken together —N(R1)R2 can form a 4-11 membered aromatic oraliphatic ring, comprising reacting a compound of formula I

with an amine of formula II [HN(R1)R2] in the presence of anon-nucleophilic auxiliary base in a solvent or mixture of solventsselected from non-nucleophilic alcohols to form a compound of formulaIII, wherein X1 is a leaving group.
 2. The method of claim 1 wherein X1and X2 are the same or different leaving groups independently selectedfrom halide, arylsulfonate, alkylsulfonate, perfluoroalkylsulfonate,arylsulfinate and alkylsulfinate.
 3. The method of claim 1 wherein X1and X2 are the same or different leaving groups and are eachindependently halides.
 4. The method of claim 1 wherein X1 and X2 arechloride.
 5. The method of claim 1 wherein one of R1 and R2 is hydrogenand the other is an aromatic group, such as e.g. optionally substitutedphenyl.
 6. The method of claim 1 wherein said non-nucleophilic auxiliarybase is N,N-diisopropyl-ethylamine.
 7. The method of claim 1 whereinsaid non-nucleophilic alcohols are tert-butanol, tert-pentanol,neo-pentanol, sec-pentanol and sec-isoamylalcohol.
 8. The method ofclaim 1 wherein said reaction is conducted in tert-butanol as reactionsolvent.
 9. The method of claim 1 wherein said reaction is conducted ata reaction temperature from about room temperature to about boilingtemperature of the solvent(s) used.
 10. The method of claim 1 whereinsaid reaction is conducted at a reaction temperature from about 40° C.to about 80° C.
 11. The method of claim 1 wherein said reaction isconducted at about 80° C.
 12. The method of claim 1 characterized inthat said reaction is conducted without any Lewis acidic metal cation.13. The method of claim 1 further comprising the steps of precipitatingthe compound of formula III from the reaction mixture, collecting theprecipitate, washing the precipitate and drying the precipitate.
 14. Themethod of claim 1 further comprising the step of reacting said compoundof formula III with an oxygen, sulphur or nitrogen nucleophile.
 15. Themethod of claim 13 further comprising suspending the precipitate inwater after it is precipitated from the reaction mixture.
 16. The methodof claim 13 characterized in that the precipitate is a substantiallyregioisomerically pure compound of formula III.
 17. The method of claim1 characterized in that a substantially regioisomerically pure compoundof formula III is produced.